title: Amyloid beta immunization worsens iron deposits in the choroid plexus and cerebral microbleeds.
abstract: Anti-amyloid beta (Aβ) immunotherapy provides potential benefits in Alzheimer's disease patients. Nevertheless, strategies based on Aβ1-42 peptide induced encephalomyelitis and possible microhemorrhages. These outcomes were not expected from studies performed in rodents. It is critical to determine if other animal models better predict side effects of immunotherapies. Mouse lemur primates can develop amyloidosis with aging. Here we used old lemurs to study immunotherapy based on Aβ1-42 or Aβ-derivative (K6Aβ1-30). We followed anti-Aβ40 immunoglobulin G and M responses and Aβ levels in plasma. In vivo magnetic resonance imaging and histology were used to evaluate amyloidosis, neuroinflammation, vasogenic edema, microhemorrhages, and brain iron deposits. The animals responded mainly to the Aβ1-42 immunogen. This treatment induced immune response and increased Aβ levels in plasma and also microhemorrhages and iron deposits in the choroid plexus. A complementary study of untreated lemurs showed iron accumulation in the choroid plexus with normal aging. Worsening of iron accumulation is thus a potential side effect of Aβ-immunization at prodromal stages of Alzheimer's disease, and should be monitored in clinical trials.
authors.affiliation: CEA, DSV, I2BM, MIRCen, 18 route du panorama, 92265 Fontenay-aux-Roses cedex, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Joseph-Mathurin
authors.forename: Olène
authors.initials: O
authors.lastname: Dorieux
authors.forename: Stéphanie G
authors.initials: SG
authors.lastname: Trouche
authors.forename: Allal
authors.initials: A
authors.lastname: Boutajangout
authors.forename: Audrey
authors.initials: A
authors.lastname: Kraska
authors.forename: Pascaline
authors.initials: P
authors.lastname: Fontès
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Verdier
authors.forename: Einar M
authors.initials: EM
authors.lastname: Sigurdsson
authors.forename: Nadine
authors.initials: N
authors.lastname: Mestre-Francés
authors.forename: Marc
authors.initials: M
authors.lastname: Dhenain
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000097:blood / Q000633:toxicity; D000818:Animals; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology*; D016565:Cheirogaleidae; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D007091:Image Processing, Computer-Assisted; D007114:Immunization / Q000009:adverse effects*; D007136:Immunoglobulins / Q000097:blood; D007501:Iron / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D010446:Peptide Fragments / Q000009:adverse effects / Q000097:blood / Q000276:immunology / Q000633:toxicity; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011135:Polysaccharides, Bacterial / Q000276:immunology; D013223:Statistics as Topic; D013997:Time Factors
chemical_list: D000276:Adjuvants, Immunologic; D016229:Amyloid beta-Peptides; D007136:Immunoglobulins; C027537:K6-antigen; D010446:Peptide Fragments; D011135:Polysaccharides, Bacterial; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D007501:Iron
keywords: ARIA (amyloid imaging related abnormalities); Aging; Alzheimer's disease; Aβ-immunization; Choroid plexus; Iron; Lemur; MRI; Microcebus murinus; Microhemorrhages; Primate